PROJECT SUMMARY This is an administrative supplement to the parent R01 AI052116 ?SPATIOTEMPORAL CONTROL OF T CELL SYNAPSE STABILIZATION AND SIGNALING? which for my entire career has been my central grant for studies of T cell interactions leading to tolerance or activation. Here, we apply our considerable immune and tissue-immune experience towards generating and exploiting a RapidPath platform to find rapid actionable immunotherapeutic targets for COVID-19 patients for limiting damage due to SARS-CoV-2 infections. In aim 1 of this study, we will build a lung plus virus plus immune platform in which the role of specific T cells of different activation status ?alone and through their modulation of myeloids cells?will be assessed in the response of damage to lung epithelium plus/minus endothelium (organoid, with Roose/Gordon and lung slice with Looney). This supplement will interact intensely with parallel studies of those labs and also with ongoing studies that will also leverage RapidPath but are not in this first cohort of applications. This will provide `best in class' model systems in human biology and will leverage our collective expertise. In aim 2 of this study, we will test a panel of immunomodulatory drugs to determine if acute exposure to them can modulate lung damage, likely through modulating myeloid biology. The net result will be validated immunotherapeutic paths in robust pre-clinical human systems that recapitulate key features of COVID-19.